Fairfield, Heather, Falank, Carolyne, Harris, Elizabeth, Demambro, Victoria, McDonald, Michelle, Pettitt, Jessica A., Mohanty, Sindhu T., Croucher, Peter, Kramer, Ina, Kneissel, Michaela, Rosen, Clifford J. and Reagan, Michaela R. (2017) The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis. Journal of cellular physiology.

Abstract

The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt-inhibitory molecule secreted from bone matrix-embedded osteocytes, can induce adipogenesis in 3T3-L1 cells, mouse ear- and BM-derived MSCs, and human BM-derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre-adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM-adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti-sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications.

Item Type:	Article
Keywords:	bone marrow adipose, bone marrow microenvironment, osteocyte-derived factors, sclerostin
Date Deposited:	12 Sep 2017 00:45
Last Modified:	12 Sep 2017 00:45
URI:	https://oak.novartis.com/id/eprint/32790